The present invention relates to novel analgesic pharmaceutical compositions containing free base or pharmaceutically acceptable salts of nalbuphine and/or nalbuphine ester, an oily substance, and a solubility-assisting agent. In particular, the present invention relates to orally administered nalbuphine and/or nalbuphine ester which demonstrates long lasting effect and greater bioavailability for pain relief in animals. The preferred oily substance is sesame oil. The preferred solubility-assisting agent is benzyl benzoate.
Nalbuphine is a synthetic opiate agonist-antagonist that is chemically related to both naloxone, a narcotic antagonist, and oxymorphone, a potent narcotic analgesic. Nalbuphine simultaneously exhibits a dual action of agonism and antagonism towards opioids-receptors. Schmidt, W. F. et al., Drug Alcohol Depend., Vol. 14, page 339 (1985). Opiate receptors include mu, kappa, and delta, which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (mu). Nalbuphine acts on specific opiate-receptor subtypes: it is a potent mu-antagonist with less dysphoric effects, and its agonistic effects at kappa1- and kappa3-receptors provide analgesia.
Actions of nalbuphine at the kappa-receptors produce alterations in the perception of pain as well as the emotional response to pain, possibly by altering the release of neurotransmitters from afferent nerves sensitive to painful stimuli. As an adjunct to anesthesia, nalbuphine protects against the hemodynamic responses to stress produced by surgery. Additionally, nalbuphine paradoxically produces opiate withdrawal if administered to opiate-dependent patients, which is a function of antagonism at the mu-receptor. Stimulation at mu-receptor produces respiratory depression. However, nalbuphine causes less respiratory depression than morphine or related agents.
Nalbuphine is used to treat moderate to severe pain associated with acute and chronic medical disorders such as cancer, renal or biliary colic, migraine or vascular headaches, and surgical pain. Nalbuphine is effective in control of severe and deep pain caused by cardiac, pulmonary, abdominal, osteopathia, and obstetrical surgery, severe burn injury, and the terminal stages of cancer via various administration routes, such as intramuscular, intravenous, intrathecal. The FDA approved nalbuphine in 1979.
Compared with conventional analgesics, nalbuphine drastically reduces induction of addiction and accretion of dosage in patients. In addition, Nalbuphine has decreased inhibition on respiratory system. Some evidence suggests that nalbuphine depressant effects on the respiratory system do not increase proportionately with increasing doses, which makes the drug safer in patients at risk from respiratory depression. However, the duration of Nalbuphine action is short, which is not enough to relieve the severe pain.
Broekkamp et al., J. Pharm. Pharmacol., Vol. 40, 434 (1988), proposes a long-acting mechanism by ester-type prodrugs. The drugs are esterified with fatty acids of different carbon numbers resulting in an increase in lipophilicity of the prodrugs. When the prodrugs are given intramuscularly, the release rates are decreased and the duration of action is prolonged. Ester-type prodrugs are hydrolyzed by esterases in the body to yield increase of mother compounds in vivo. Esterases exist in many tissues and organs including blood, liver, heart, brain, kidneys, lungs, and muscles. The pharmacological effect and safety of the ester type prodrug and the mother compound are reported to be the same.
Additionally, the conventional form of nalbuphine, nalbuphine hydrochloride (nalbuphine-HCl), is not practical for oral administration, because the bioavailability through oral administration is less than 5%. Thus, nalbuphine-HCl has not been made available in a form for oral administration. In a paper published in 1988 by Harrelson J. C. and Wong Y. J., Xenobiotica (1988), 18:1239-1247, the researchers found that acetylsalicylate ester prodrug of nalbuphine improved the bioavailability through oral administration, which also masked the bitter taste of nalbuphine-HCl. However, the bioavailability of the acetylsalicylate ester prodrug is only 16%, which is still not effective enough for oral administration. In another paper published in 1988 by Hussain, M. A. et al., J. Pharm. Sciences, 75:218-219 (1986), the researchers found that buccal delivery could improve the bioavailability of the opioids prodrugs to as high as 35-50%. Nevertheless, buccal delivery is not as convenient and acceptable as oral administration. Therefore, pharmaceutical compositions containing nalbuphine base with long-acting effects and high bioavailability for oral administration are desirable.
Recently, Yoa-Pu et al., U.S. Pat. No. 5,750,534 (the ""534 patent), disclose a nalbuphine prodrug which contains nalbuphine monoester, wherein the R in the ester group (RCO) is a straight or branched alkyl group of 2-36 carbon atoms or a phenyl group. The nalbuphine monoester prodrug is characterized as having prolonged analgesic duration. The ""534 patent is herein incorporated by reference.
Hu et al., U.S. Pat. No. 6,225,321 (the ""321 patent), disclose yet another nalbuphine prodrug which contains nalbuphine polyester having a generic formula of Rxe2x80x94[COxe2x80x94NAL]n, wherein n is an integer from 2-4 and R in the ester group is a saturated or nonosaturated, substituted or unsubstituted, aliphatic or aromatic group having 1 to 40 carbon atoms. The nalbuphine polyester is designed as a soft drug which can maintain analgesic effect in animal body for 4-5 days. The ""321 patent is herein incorporated by reference.
In the sections to be presented below, the present invention provides a pharmaceutical composition which, by incorporating the nalbuphine ester prodrugs as described in the ""534 patent and the ""321 patent as the active ingredient, together with an oily substance and a solubility-assisting agent, can be administered orally. The pharmaceutical composition of the present invention not only provides long-lasting effect but also demonstrates greater bioavailability for pain relief in animal body.
The present invention provides pharmaceutical compositions which contain (1) an active ingredient, which is a nalbuphine or a nalbuphine ester prodrug, or the pharmaceutically acceptable salts of nalbuphine or nalbuphine ester prodrug; (2) an oily substance, and (3) a solubility-assisting agent. The pharmaceutical composition is preferably administered orally.
There are two kinds of nalbuphine ester prodrugs, which are nalbuphine monoester and nalbuphine polyester. Examples of nalbuphine monoester include, but are not limited to, nalbuphine propionate, nalbuphine pivalate, nalbuphine enanthate, nalbuphine decanoate, nalbuphine behenate, nalbuphine erucicate, nalbuphine arachidate, and nalbuphine benzoate. Examples of nalbuphine polyester include, but are not limited to, adipoyl dinalbuphine ester, sebacoyl dinalbuphine ester, 1,3-cyclohexane diacid dinalbuphine ester, docosanodic dinalbuphine ester, 3,3-dimethylglutaric diacid dinalbuphine ester, trinalbuphine trimesoyl ester, 1,3,5-cyclohexane triacid trinalbuphine ester, pyromellitoyl tetranalbuphine ester. Among the nalbuphine ester prodrugs, sebacoyl dinalbuphine ester (SDN) is the most preferable one to be used in oral administration.
The oily substance is preferably a vegetable oil, and more favorably sesame oil, soybean oil or peanut oil. The most favorable vegetable oil is sesame oil. The solubility-assisting agent is preferably benzyl benzoate.
The pharmaceutical composition of the present invention contains about 1% to 15% by weight of free base or salts of nalbuphine or nalbuphine ester prodrug, preferably about 10% by weight; about 30% to 90% by weight of the oily substance, preferably about 55% by weight of sesame oil; and about 5% to 50% by weight of the solubility-assisting agent, preferably about 45% by weight of the solubility-assisting agent.
The present invention also provides a method for treating patients with severe, long lasting pain by orally administering the pharmaceutical composition described above to patients. The severe, long lasting pain suffered by patients is caused by cardiac, pulmonary, osteopathia, obstetrical surgery, bum injury, or terminal stage of cancer.
The nalbuphine ester prodrug-containing oral pharmaceutical composition demonstrates high bioavailability in vivo and prolong pain-killing effect. Also, because the pharmaceutical composition provided in the present invention can be administered orally, it is more convenient than the traditional use of nalbuphine, i.e., by injection or buccal delivery.